Abstract
The transcription factor IRF5 has been implicated as a therapeutic target for the autoimmune disease systemic lupus erythematosus (SLE). However, IRF5 activation status during the disease course and the effects of IRF5 inhibition after disease onset are unclear. Here, we show that SLE patients in both the active and remission phase have aberrant activation of IRF5 and interferon-stimulated genes. Partial inhibition of IRF5 is superior to full inhibition of type I interferon signaling in suppressing disease in a mouse model of SLE, possibly due to the function of IRF5 in oxidative phosphorylation. We further demonstrate that inhibition of IRF5 via conditional Irf5 deletion and a newly developed small-molecule inhibitor of IRF5 after disease onset suppresses disease progression and is effective for maintenance of remission in mice. These results suggest that IRF5 inhibition might overcome the limitations of current SLE therapies, thus promoting drug discovery research on IRF5 inhibitors.
Highlights
The transcription factor IRF5 has been implicated as a therapeutic target for the autoimmune disease systemic lupus erythematosus (SLE)
To find out whether the activation status of IRF5 has relevance to SLE disease activity, we assessed IRF5 nuclear translocation in immune cells isolated from peripheral blood of SLE patients (Fig. 1a, Supplementary Fig. 1a–c, and Supplementary Table 1)
Our method, which evaluates the IRF5 nuclear/cytoplasmic ratio, clearly distinguished IRF5 undergoing nuclear translocation (Fig. 1a and Supplementary Fig. 1a–c). Consistent with another report[24], the proportion of cells in which IRF5 was translocated into the nucleus was higher in monocytes from SLE patients than those from healthy donors (Fig. 1b and Supplementary Fig. 2)
Summary
The transcription factor IRF5 has been implicated as a therapeutic target for the autoimmune disease systemic lupus erythematosus (SLE). The similar dynamics of IRF5 activation and ISG expression in SLE patients prompted us to investigate whether the inhibition of IRF5 exerts only the action that equals the effect of inhibition of type I IFNs. For this purpose, we used Lyn-deficient (Lyn−/−) mice as a mouse SLE model.
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